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Delivery construct for antisense nucleic acids and methods of use

a technology of nucleic acid and delivery construct, which is applied in the direction of organic chemistry, genetic material ingredients, peptide/protein ingredients, etc., can solve the problems of limited effective use of antisense oligonucleotides, narrow therapeutic index of chemotherapeutic agents, and disadvantages of systemic toxicity of conventional chemotherapy for neoplastic and virus-related diseases

Inactive Publication Date: 2005-01-27
THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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  • Abstract
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Benefits of technology

[0008] The present invention provides a novel nucleic acid construct for delivery of antisense targeting sequences for inhibition of selected genes in a cell. The ...

Problems solved by technology

For example, conventional chemotherapy for neoplastic and virus-related diseases has the disadvantage of systemic toxicity.
The therapeutic index for chemotherapeutic agents is relatively narrow, since such agents are unable to distinguish between normal and diseased cells.
Unfortunately, the effective use of antisense oligonucleotides has been limited due to several problems.
Disadvantages include the transient nature of ODNs, and their toxicity and propensity for producing non-sequence specified biological effects.
Other disadvantages include low expression or limited stability of complementary RNAs which result in their nonspecific targeting or low efficiency of target inhibition.
Antisense oligonucleotides are often poorly taken up by cells and therefore may never reach their target site.
This technique works well in the laboratory, however, it cannot be applied to patients.
Many of the studies with antisense show that gene expression is suppressed by 80-90% of the normal level, however, such reduction is not typically sufficient to reduce the biological effect, e.g., 10-20% expression is sufficient to maintain the biological function sought to suppress.

Method used

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  • Delivery construct for antisense nucleic acids and methods of use
  • Delivery construct for antisense nucleic acids and methods of use
  • Delivery construct for antisense nucleic acids and methods of use

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[0062] An antisense expression construct was constructed that incorporates several potentially enhancing features. The pU1 / FIB vector was constructed on the backbone of the pZeoSV (Invitrogen) prokaryotic / eukaryotic expression vector. The SV40 promoter, polyadenylation site and polylinker were excised from pZeoSV at the BamHI sites. A U1 snRNA expression cassette cloned into pUC13 was excised with BamHI digestion and ligated into the BamHI sites of the modified pZeoSV. Two rounds of site-directed mutagenesis (Deng, et al., Anal. Biochem., 200, 81; 1992) were then performed to change four nucleotides flanking the Sm protein restriction sites (pZeoU1EcoSpe). Complementary oligonucleotides that encode the antisense>core=sequence, shown in FIG. 1, including the 24 highly conserved nucleotides of hammerhead ribozymes (Cech, et al., Ann. Rev. Biochem., 55:599, were synthesized and annealed at 40E C such that the remaining 5′ and 3′ overhangs were exactly complementary to the overhangs lef...

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Abstract

A novel nucleic acid construct for delivery of antisense targeting sequences is provided. The construct includes intact stem loop structures and an antisense nucleic acid. Optionally, a ribozyme nucleic acid is included in the construct. The construct is useful for inhibition of selected genes in a cell. This allele-specific targeting is also useful in combination with replacement gene therapy.

Description

FIELD OF THE INVENTION [0001] This invention relates generally to the field of delivery vehicles for nucleic acid molecules and specifically to a novel construct for delivery of antisense targeting sequences to a cell. BACKGROUND OF THE INVENTION [0002] The use of antisense oligonucleotides offers advantages over other therapeutic regimes due to their potential for target specificity. For example, conventional chemotherapy for neoplastic and virus-related diseases has the disadvantage of systemic toxicity. The therapeutic index for chemotherapeutic agents is relatively narrow, since such agents are unable to distinguish between normal and diseased cells. Antisense oligonucleotides have the potential to be many orders of magnitude more specific than traditional drugs due to their greater number of interactions with a particular target site. In theory, an oligonucleotide of more than 15-17 nucleotides in length could have the base pairing specificity to interact with only one target g...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K48/00C12N15/113
CPCA01K2217/05A61K38/00A61K48/00C12N2310/53C12N2310/111C12N2310/121C12N15/113
Inventor DIETZ, HARRY
Owner THE JOHN HOPKINS UNIV SCHOOL OF MEDICINE
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